by Lindy Keane Carter
The buildup of amyloid plaques in the brain is one of the causes of the neuronal loss and memory deficits of Alzheimer’s disease (AD). For years, researchers have focused on one kind of enzyme that produces the plaques—the β-secretase (BACE-1). But now an MUSC scientist and his collaborators have established in mouse models that a different enzyme is actually the primary plaque producer. Furthermore, they have identified a drug compound that shows promise for being developed into an inhibitor of that enzyme.
Mark S. Kindy, PhD, Associate Chair in Regenerative Medicine and Cell Biology at MUSC, was one of the five researchers who reported their findings in several journals, including the Journal of Alzheimer’s Disease.1 “We have identified cathepsin B as the primary β-secretase, not BACE-1,” says Kindy. “This explains why BACE-1 inhibitors have not been successful in the past.”
This finding advances scientific understanding of how to better disable the main culprit in one of the causes of AD.
The promising drug compound is E64d, a cysteine protease inhibitor of cathepsin B that has already been shown in clinical trials to be safe in humans. No other AD therapeutic research program is known to be investigating this kind of inhibitor.
“If we can inhibit the cathepsin B activity, we may be able to slow the progression of Alzheimer’s disease and extend years of healthier life for many people,” Kindy explains. Currently, AD drugs only treat symptoms. There are no drugs that slow, prevent, or cure the disease.
Another distinction of this group’s research was the use of oral administration of the drug, as opposed to the brain injections done in earlier mouse studies. This finding is important for potential future human use of the drug because oral administration is simpler.
β-amyloid plaques are the hallmark of AD. Their creation begins when amyloid-β (Aβ) peptides are released by the “cutting” of a larger protein called amyloid precursor protein (APP). The enzyme “scissor” is β-secretase, of which there are several kinds. BACE-1 was thought to be the primary β-secretase and cathepsin B a secondary. As Aβ peptides collect in the brain, they form plaques in the regions responsible for memory. In addition, cathepsin B is responsible for the generation of a pyroglutamate form of Ab that is important in the development of the disease process. The drug E64d inhibits the “scissors” from cutting APP into smaller toxic peptides and prevents the production of Ab pyroglutamate. Researchers also confirmed cathepsin B as the right target when they tested mice with a gene knockout of BACE-1 vs mice with a gene knockout of cathepsin B. They found that the mice with the latter had reduced AD-like pathology. Moreover, cathepsin B knockout as well as E64d treatment were shown to improve memory deficit in mice.
The research team will now seek to modify E64d so that it, or other iterations of it, will more effectively inhibit cathepsin B and produce fewer side effects, with their goal being to eventually move into clinical trials. Funding for the initial research was provided in part by the Veterans Health Administration, the National Institutes of Health, and the Alzheimer’s Association.
1 Hook G, Yu J, Toneff T, Kindy M, et al. Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer’s Disease therapeutic. J Alzheimers Dis. 2014;41(1): 129-149.
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